Molecular and Cellular Biochemistry

, Volume 366, Issue 1–2, pp 269–275 | Cite as

Clinical relevance of cyclooxygenase-2 and matrix metalloproteinases (MMP-2 and MT1-MMP) in human breast cancer tissue

  • Mohammad A. Mohammad
  • Ahmed A. Zeeneldin
  • Zakaria Y. Abd Elmageed
  • Ebtsam H. Khalil
  • Said M. E. Mahdy
  • Hayat M. Sharada
  • Sabry K. Sharawy
  • Abdel-Hady A. Abdel-WahabEmail author


Breast cancer (BC) is the most common neoplasm among women in most developed countries, including Egypt. Elevated levels of certain proteins in human BC are associated with unfavorable prognosis and progressive stages of the disease. The aim of our study was to evaluate the protein expression profile and prognostic significance of cyclooxygenase-2 (COX-2), matrix metalloproteinase-2 (MMP-2), MMP-9 and membrane type 1-MMP (MT1-MMP) and their interaction in operable BC patients. The protein expression of COX-2, MMP-2 and MT1-MMP were evaluated by western blot technique, whereas enzymatic activity of MMP-2 and MMP-9 was determined by zymography in 47 breast cancer patients as well as normal adjacent tissues. Also, the correlation between these proteins and age, tumor size, LN stage, TNM stage, estrogen receptor, progesterone receptor, disease-free survival, and overall survival (OS) has been investigated. As compared to adjacent normal tissues, COX-2, MMP-2 and MT1-MMP were over-expressed in 43, 64, and 60 % of tumor tissues, respectively. In the same pattern, the activity of MMP-2 (62 %) and MMP-9 (45 %) was elevated in BC tissues. Multivariate analysis showed a positive correlation between the protein expression of COX-2, MMP-2, and MT1-MMP and the activity of MMP-2 and MMP-9 in BC patients. However, the enzymatic activity showed no correlation with clinicopathological features. This study confirms the preclinical evidence that COX-2 increased the expression of MT1-MMP, which in turn activates MMP-2. The lack of correlation with clinicopathological features, OS or disease-free survival ascertains the complexity of tumor progression and metastasis with many pro- and counter regulatory factors.


Breast cancer Cox-2 MMPs MT1-MMP Western blot Zymography 



This work was supported by grant from National Cancer Institute (NCI-48019), Cairo University, Cairo, Egypt.

Conflict of interest

We declare that we have no conflict of interest for any of the authors including financial, personal or other relationships with other people or organization.


  1. 1.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127(12):2893–2917PubMedCrossRefGoogle Scholar
  2. 2.
    Hortobagyi GN, de la Garza Salazar J, Pritchard K, Amadori D, Haidinger R, Hudis CA, Khaled H, Liu MC, Martin M, Namer M, O’Shaughnessy JA, Shen ZZ, Albain KS (2005) The global breast cancer burden: variations in epidemiology and survival. Clin Breast Cancer 6:391–401PubMedCrossRefGoogle Scholar
  3. 3.
    Dey S, Soliman AS, Hablas A, Seifeldein IA, Ismail K, Ramadan M, El-Hamzawy H, Wilson ML, Banerjee M, Boffetta P, Harford J, Merajver SD (2010) Urban-rural differences in breast cancer incidence in Egypt (1999–2006). Breast 19:417–423PubMedCrossRefGoogle Scholar
  4. 4.
    Institute ENC: Cancer registry 2002–2003 by Egyptian NCI. In: NCI Egypt, 2003, pp 45–46Google Scholar
  5. 5.
    Wymann MP, Schneiter R (2008) Lipid signalling in disease. Nat Rev Mol Cell Biol 9:162–176PubMedCrossRefGoogle Scholar
  6. 6.
    Maitra A, Ashfaq R, Gunn CR, Rahman A, Yeo CJ, Sohn TA, Cameron JL, Hruban RH, Wilentz RE (2002) Cyclooxygenase 2 expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasia: an immunohistochemical analysis with automated cellular imaging. Am J Clin Pathol 118:194–201PubMedCrossRefGoogle Scholar
  7. 7.
    Dempke W, Rie C, Grothey A, Schmoll HJ (2001) Cyclooxygenase-2: a novel target for cancer chemotherapy? J Cancer Res Clin Oncol 127:411–417PubMedCrossRefGoogle Scholar
  8. 8.
    Ristimaki A, Sivula A, Lundin J, Lundin M, Salminen T, Haglund C, Joensuu H, Isola J (2002) Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res 62:632–635PubMedGoogle Scholar
  9. 9.
    McCawley LJ, Matrisian LM (2000) Matrix metalloproteinases: multifunctional contributors to tumor progression. Mol Med Today 6:149–156PubMedCrossRefGoogle Scholar
  10. 10.
    Reno F, Sabbatini M, Stella M, Magliacani G, Cannas M (2005) Effect of in vitro mechanical compression on epilysin (matrix metalloproteinase-28) expression in hypertrophic scars. Wound Repair Regen 13:255–261PubMedCrossRefGoogle Scholar
  11. 11.
    Itoh Y, Seiki M (2006) MT1-MMP: a potent modifier of pericellular microenvironment. J Cell Physiol 206:1–8PubMedCrossRefGoogle Scholar
  12. 12.
    Sakata K, Shigemasa K, Nagai N, Ohama K (2000) Expression of matrix metalloproteinases (MMP-2, MMP-9, MT1-MMP) and their inhibitors (TIMP-1, TIMP-2) in common epithelial tumors of the ovary. Int J Oncol 17:673–681PubMedGoogle Scholar
  13. 13.
    Giannelli G, Bergamini C, Marinosci F, Fransvea E, Quaranta M, Lupo L, Schiraldi O, Antonaci S (2002) Clinical role of MMP-2/TIMP-2 imbalance in hepatocellular carcinoma. Int J Cancer 97:425–431PubMedCrossRefGoogle Scholar
  14. 14.
    Strongin AY, Collier I, Bannikov G, Marmer BL, Grant GA, Goldberg GI (1995) Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease. J Biol Chem 270:5331–5338PubMedCrossRefGoogle Scholar
  15. 15.
    Davidson B, Goldberg I, Gotlieb WH, Kopolovic J, Ben-Baruch G, Nesland JM, Reich R (2002) The prognostic value of metalloproteinases and angiogenic factors in ovarian carcinoma. Mol Cell Endocrinol 187:39–45PubMedCrossRefGoogle Scholar
  16. 16.
    Ogura S, Ohdaira T, Hozumi Y, Omoto Y, Nagai H (2007) Metastasis-related factors expressed in pT1 pN0 breast cancer: assessment of recurrence risk. J Surg Oncol 96:46–53PubMedCrossRefGoogle Scholar
  17. 17.
    Herron GS, Banda MJ, Clark EJ, Gavrilovic J, Werb Z (1986) Secretion of metalloproteinases by stimulated capillary endothelial cells. II. Expression of collagenase and stromelysin activities is regulated by endogenous inhibitors. J Biol Chem 261:2814–2818PubMedGoogle Scholar
  18. 18.
    Coradini D, Daidone MG (2004) Biomolecular prognostic factors in breast cancer. Curr Opin Obstet Gynecol 16:49–55PubMedCrossRefGoogle Scholar
  19. 19.
    Parrett MLHR, Joarder FS, Ross MS, Clausen KP, Robertson FM (1997) Cyclooxygenase-2 gene expression in human breast cancer. Int J Oncol 10:503–507PubMedGoogle Scholar
  20. 20.
    Hwang D, Scollard D, Byrne J, Levine E (1998) Expression of cyclooxygenase-1 and cyclooxygenase-2 in human breast cancer. J Natl Cancer Inst 90:455–460PubMedCrossRefGoogle Scholar
  21. 21.
    Cejas PG-CM, Casado E, Barriusoa J, Fresnoa JA, Díaza E, Belda-Iniestaa C, Castroa J, Espinosaa E, Zamoraa P, Feliua J, Redondoa A, Hardissonb DA, González-Baróna M (2005) Localisation of COX-2 protein is different in breast ductal carcinoma and adjacent non-tumour ductal epithelium. Clin Transl Oncol 7:239–243PubMedCrossRefGoogle Scholar
  22. 22.
    Ito H, Duxbury M, Benoit E, Clancy TE, Zinner MJ, Ashley SW, Whang EE (2004) Prostaglandin E2 enhances pancreatic cancer invasiveness through an Ets-1-dependent induction of matrix metalloproteinase-2. Cancer Res 64:7439–7446PubMedCrossRefGoogle Scholar
  23. 23.
    Mohammad AM, Abdel HA, Abdel W, Ahmed AM, Wael T, Eiman G (2006) Expression of cyclooxygenase-2 and 12-lipoxygenase in human breast cancer and their relationship with HER-2/neu and hormonal receptors: impact on prognosis and therapy. Indian J Cancer 43:163–168PubMedCrossRefGoogle Scholar
  24. 24.
    Zeeneldin AA, Mohamed AM, Abdel HA, Taha FM, Goda IA, Abodeef WT (2009) Survival effects of cyclooxygenase-2 and 12-lipooxygenase in Egyptian women with operable breast cancer. Indian J Cancer 46:54–60PubMedCrossRefGoogle Scholar
  25. 25.
    Spizzo G, Gastl G, Wolf D, Gunsilius E, Steurer M, Fong D, Amberger A, Margreiter R, Obrist P (2003) Correlation of COX-2 and Ep-CAM overexpression in human invasive breast cancer and its impact on survival. Br J Cancer 88:574–578PubMedCrossRefGoogle Scholar
  26. 26.
    Park K, Han S, Shin E, Kim HJ, Kim JY (2006) Cox-2 expression on tissue microarray of breast cancer. Eur J Surg Oncol 32:1093–1096PubMedCrossRefGoogle Scholar
  27. 27.
    Kelly LM, Hill AD, Kennedy S, Connolly EM, Ramanath R, Teh S, Dijkstra B, Purcell R, McDermott EW, O’Higgins N (2003) Lack of prognostic effect of Cox-2 expression in primary breast cancer on short-term follow-up. Eur J Surg Oncol 29:707–710PubMedCrossRefGoogle Scholar
  28. 28.
    Nakopoulou L, Mylona E, Papadaki I, Kapranou A, Giannopoulou I, Markaki S, Keramopoulos A (2005) Overexpression of cyclooxygenase-2 is associated with a favorable prognostic phenotype in breast carcinoma. Pathobiology 72:241–249PubMedCrossRefGoogle Scholar
  29. 29.
    McCarthy K, Bustin SA, Ogunkolade B, Khalaf S, Laban CA, McVittie CJ, Carpenter R, Jenkins PJ (2006) Cyclo-oxygenase-2 (COX-2) mRNA expression and hormone receptor status in breast cancer. Eur J Surg Oncol 32:707–709PubMedCrossRefGoogle Scholar
  30. 30.
    Nakopoulou L, Tsirmpa I, Alexandrou P, Louvrou A, Ampela C, Markaki S, Davaris PS (2003) MMP-2 protein in invasive breast cancer and the impact of MMP-2/TIMP-2 phenotype on overall survival. Breast Cancer Res Treat 77:145–155PubMedCrossRefGoogle Scholar
  31. 31.
    Tetu B, Brisson J, Wang CS, Lapointe H, Beaudry G, Blanchette C, Trudel D (2006) The influence of MMP-14, TIMP-2 and MMP-2 expression on breast cancer prognosis. Breast Cancer Res 8:R28PubMedCrossRefGoogle Scholar
  32. 32.
    Shah FD, Shukla SN, Shah PM, Shukla HK, Patel PS (2009) Clinical significance of matrix metalloproteinase 2 and 9 in breast cancer. Indian J Cancer 46:194–202PubMedCrossRefGoogle Scholar
  33. 33.
    Sivula A, Talvensaari-Mattila A, Lundin J, Joensuu H, Haglund C, Ristimaki A, Turpeenniemi-Hujanen T (2005) Association of cyclooxygenase-2 and matrix metalloproteinase-2 expression in human breast cancer. Breast Cancer Res Treat 89:215–220PubMedCrossRefGoogle Scholar
  34. 34.
    Stankovic S, Konjevic G, Gopcevic K, Jovic V, Inic M, Jurisic V (2010) Activity of MMP-2 and MMP-9 in sera of breast cancer patients. Pathol Res Pract 206:241–247PubMedCrossRefGoogle Scholar
  35. 35.
    Li HC, Cao DC, Liu Y, Hou YF, Wu J, Lu JS, Di GH, Liu G, Li FM, Ou ZL, Jie C, Shen ZZ, Shao ZM (2004) Prognostic value of matrix metalloproteinases (MMP-2 and MMP-9) in patients with lymph node-negative breast carcinoma. Breast Cancer Res Treat 88:75–85PubMedCrossRefGoogle Scholar
  36. 36.
    Sato H, Takino T, Okada Y, Cao J, Shinagawa A, Yamamoto E, Seiki M (1994) A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature 370:61–65PubMedCrossRefGoogle Scholar
  37. 37.
    Schirrmacher V (1985) Cancer metastasis: experimental approaches, theoretical concepts, and impacts for treatment strategies. Adv Cancer Res 43:1–73PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Mohammad A. Mohammad
    • 1
  • Ahmed A. Zeeneldin
    • 2
  • Zakaria Y. Abd Elmageed
    • 3
  • Ebtsam H. Khalil
    • 4
  • Said M. E. Mahdy
    • 4
  • Hayat M. Sharada
    • 4
  • Sabry K. Sharawy
    • 1
  • Abdel-Hady A. Abdel-Wahab
    • 1
    Email author
  1. 1.Department of Cancer BiologyNational Cancer Institute, Cairo UniversityCairoEgypt
  2. 2.Department of Medical OncologyNational Cancer Institute, Cairo UniversityCairoEgypt
  3. 3.Department of Urology and OncologyTulane University Medical CenterNew OrleansUSA
  4. 4.Department of Chemistry, Faculty of ScienceHelwan UniversityHelwanEgypt

Personalised recommendations